Fibrosis of tissue is caused by the excessive production and accumulation in tissue of extracellular matrix, which is mainly collagen. When tissue is damaged by a stimulus such as oxidative stress, hypoxia, inflammation, or apoptosis, damaged tissue is repaired by replacement with extracellular matrix, but in the case of the damage being serious or in the case of such stimulation becoming chronic, the accumulation of extracellular matrix becomes excessive, and the tissue cannot perform its function sufficiently. Fibrosis is seen in various types of organs, such as the liver, pancreas, lung, kidney, bone marrow, and heart, and it is thought that collagen-producing cells such as myofibroblasts are related to a disease state. Conventionally, it is though that fibrosis is an irreversible phenomenon and that once tissue has become fibrotic it does not return to its original state, but recently, there have been some reports suggesting that fibrosis is reversible, and that when the above-mentioned fibrotic stimulus disappears, the extracellular matrix accumulated in the tissue decreases (see Non-Patent Documents 1 to 3).
However, there have been no detailed reports regarding what is specifically happening in the tissue after pathological accumulation of extracellular matrix decreases, and it has been completely unknown until now for regeneration of normal tissue to occur in such fibrotic tissue or for regeneration of normal tissue to be possible.
Furthermore, the fibrosis of tissue not only includes fibroses for which the cause of the disease is clear and can be removed, such as fibrosis derived from viral infection, drinking alcohol, drugs, etc., but also includes fibroses for which the direct cause of the disease is unclear, such as for example cryptogenic cirrhosis, idiopathic pulmonary fibrosis, or idiopathic myelofibrosis, and those for which the direct cause of the disease is known but the origin of the cause of the disease is unclear or is difficult to remove, such as for example primary biliary cirrhosis, nonalcoholic steatohepatitis (NASH)-derived hepatic fibrosis, and primary sclerosing cholangitis. Tissue with the presence of such fibrosis, for which it is difficult to remove the cause of the disease, is in a state in which it is always exposed to a fibrotic stimulus, but it has been completely unknown until now that the pathological accumulation of extracellular matrix in such fibrotic tissue can be reduced, and certainly not known that the tissue can be regenerated.